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to human adenoviruses so the immune response to vector is primary, while most humans have preexisting immunity to Ad5 and therefore the immune response is secondary. There are differences in antigen processing and presentation between inbred animals and humans, and the effects of some E3 genes are limited to human MHC proteins. In addition, the potential effects of RCA are different because human adenoviruses do not replicate in rodent cells, but some human Ad are actually oncogenic in rodents but not in humans.

The final step of commencing a clinical study is obtaining regulatory approval, which is also complex. Gene therapy in general and adenovirus in particular are generally perceived as being particularly hazardous and therefore multiple levels of review are required. The local Institutional Review Board (IRB) and Institutional Biosafety Committee (IBC) must approve, as well as the Recombinant DNA Advisory Committee of the National Institutes of Health. The Investigational New Drug application to the FDA represents the last phase of approval. Each group has slightly different concerns, and the final result is a protocol that is conservative yet likely to be safe, ethical and informative. All revisions to the protocol must be approved by all regulatory groups, therefore keeping the protocol current needs well-organized administration. The actual clinical study must be performed under good clinical practice with timely reporting of all adverse events to the

FDA, RAC, IRB, and IBC. In addition, many institutions have added a data safety monitoring board to further ensure the safety of gene therapy studies.

Data on models of disease in experimental animals provided sufficient basis to proceed to adenovirus vector-mediated gene transfer in humans. The first human studies were commenced in 1993, and a total of 143 studies are listed in the current update of the database of the RAC. These have generally been small phase I or phase II studies (Table 3). Although the first studies were directed at cystic fibrosis, the currently active studies are focused on cancer and cardiovascular disease. In total, 72% of the listed studies involve cancer with the same vector being studied in a number of different tumors or different patient subsets or concurrently with different concurrent therapies. In general, capsid modified vectors and second-generation vectors have not been used in humans, and it is unknown if the advantages these new vectors sometimes offer in experimental animals apply in humans.

In general, gene transfer of Ad vectors has been safe and well tolerated (133,134). The notable exception is that intravenous administration results in dose-dependent toxicity that has resulted in 1 death (135-138). This reaction is rapid and is believed to be related to the innate immune system. In addition to showing safety, several studies have shown that there is also effective delivery of the vector to the patient and subsequent

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